Preparation of pyrimido[4,5 b][1,6]naphthyridin-4(1 h)-one derivatives

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/349391514
Preparation of pyrimido[4,5-b] [1,6]naphthyridin-4(1H)-one derivatives
using a zeolite-nanogold catalyst and their in vitro evaluation as anticancer
agent
Article  in  Journal of Chemical Research · February 2021
DOI: 10.1177/1747519820988806
CITATIONS
0
READS
14
4 authors, including:
Some of the authors of this publication are also working on these related projects:
Immune Status of Pediatric Patients with hematologic malignancies against Measles, Varicella Zoster, and Hepatitis B virus; Molecular and clinical relevance View
project
Egypt COVID-19 Response Team View project
Elshimaa Eid
Cairo University
4 PUBLICATIONS   21 CITATIONS
SEE PROFILE
Samah A Loutfy
National Cancer Institute Egypt
48 PUBLICATIONS   579 CITATIONS
SEE PROFILE
All content following this page was uploaded by Elshimaa Eid on 19 February 2021.
The user has requested enhancement of the downloaded file.

Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons
Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use,
reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and
Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
https://doi.org/10.1177/1747519820988806
Journal of Chemical Research
1–8
© The Author(s) 2021
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/1747519820988806
journals.sagepub.com/home/chl
Preparation of pyrimido[4,5-b]
[1,6]naphthyridin-4(1H)-one derivatives
using a zeolite–nanogold catalyst and their
in vitro evaluation as anticancer agent
Elshimaa M Eid1
, Huwaida ME Hassaneen1
,
Samah A Loutfy2,3
and Taher Salaheldin4
Abstract
Catalysis using supported gold nanoparticles has attracted significant research interest due to their unique properties
and potential that is directly related to their particle size. An efficient one-pot, three-component procedure is developed
for the preparation of pyrimido[4,5-b][1,6]naphthyridin-4(1H)-one derivatives (4a–h) by cyclocondensation of 6-amino-
2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1), aromatic aldehydes (2), and 1-benzylpiperidin-4-one (3) in the presence
of zeolite-nano Au as a green catalyst in ethanol at 80
°C. The presented methodology has a number of advantages
including a reusable catalyst, easy access, short reaction times, high yields, and an easy work-up. The nanogold catalyst is
characterized by X-ray diffraction and transmission electron microscopy. The structures of the prepared compounds are
established by elemental analyses and spectral data (infrared, mass spectrometry, 1
H, and 13
C NMR). While molecular
docking studies show that products 4a and 4c have binding affinities with the active site of CDKs. A bio-evaluation assay
revealed that some of the products exhibit strong to moderate effects against proliferation of Huh7 in an in vitro model
of human liver cancer cells as confirmed by morphological alteration. Compounds 4c and 4a offer the lowest IC50 values
at 22.5 and 39 µM, respectively.
Keywords
CDKs, nanocomposite, pyrimido[4,5-b][1,6]naphthyridin-4(1H)-ones, zeolite-nano Au
Date received: 4 September 2020; accepted: 31 December 2020
1

Chemistry Department, Faculty of Science, Cairo University, Giza,
Egypt
2

Virology Immunology Unit, Cancer Biology Dept, National Cancer
Institute, Cairo University, Cairo, Egypt
3

Nanotechnology Research Center, The British University of Egypt,
Cairo, Egypt
988806CHL0010.1177/1747519820988806Journal of Chemical ResearchEid et al.
research-article2021
Research Paper
4
Pharmaceutical Research Institute, Albany College of Pharmacy and
Health Sciences, Albany, NY, USA
Corresponding author:
Elshimaa M Eid, Chemistry Department, Faculty of Science, Cairo
University, Giza Street, 12613 Giza, Egypt.
Email: elshimaaeid80@hotmail.com

2 Journal of Chemical Research 00(0)
Introduction
1,6-Naphthyridines have received considerable attention
because of their wide range of biological activities,1–3
including antitumor, anti-inflammatory, antimicrobial,4
and
anticonvulsant. Both pyrimidine and 1,6-naphthyridine
scaffolds have been shown to be important structural motifs
in chemistry; therefore, the preparation of pyrimidonaph-
thyridine derivatives, in which these scaffolds are merged,
might provide compounds that exhibit simultaneously the
biological properties of each moiety.4–6
Gangjee and co-workers have described the construction
of the pyrimidonaphthyridine skeleton via a multistep
reaction.7
Previously, it was reported that pyrimido[4,5-b]
[1,6]naphthyridine moieties could be synthesized effi-
ciently under microwave conditions.1
Hence, the continued
development of diverse pyrimidonaphthyridine compounds
is still in strong demand. Marjani and his team were able
to synthesize pyrimidonaphthyridine derivatives in the
presence of AgNPs under mild conditions.8
Some previ-
ously published protocols using acid,9–11
basic,1
or metal
catalysts,12
or catalyst-free protocols under microwave13
or
thermal conditions for the formation of analogs of the target
moiety. Unfortunately, all previous methods produce very
low yields; therefore, it was our aim to develop new condi-
tions based on using a nanocatalyst hoping to improve the
yields. The use of a nanocatalytic system would allow the
rapid, and selective chemical transformations coupled with
the ease of catalyst separation and recovery.14
Using a
nano-sized catalyst (high surface area), the contact between
the reactants and catalyst is increased dramatically (this
phenomenon is close to homogeneous catalysis).15,16
The
insolubility of the catalyst in the reaction solvent leads to a
heterogeneous process, and hence, the catalyst can be sepa-
rated easily from the reaction mixture (this phenomenon is
close to heterogeneous catalysis).17–20
It is known that
catalytic properties of metallic NPs are size- and shape-
dependent.21–25
It has been reported that gold nanoparticles
are stabilized and well dispersed on various supports
(metal oxides,26–31
carbon materials,32–40
metal–organic
frameworks,41–43
zeolites,44
modified aluminum,32,44–47
ionic liquids,48
etc.) and have the ability to catalyze several
reactions successfully.
Several reports have demonstrated the wide applica-
tions of zeolites as catalysts and adsorbents.49–53
These
microporous materials are three-dimensional and crystal-
line hydrated aluminosilicates,54
and are highly rigid under
dehydration.55
The important structural, physical, and
chemical properties of zeolites, with tailored channels
and cavities on the molecular scale, make them versatile
and valuable for such broad applications as adsorbents
and catalysts in industrial, agricultural, and environmen-
tal applications.56
Moreover, zeolite-nanogold possesses
high thermal stability and plays the dual role of stabiliz-
ing the nanoparticles against sintering and their distinct
pore structure can facilitate shape-selective catalysis.
Zeolite nanoshell encapsulating gold nanoparticles has
successfully been employed for cyclohexane oxidation,
and these catalysts show better conversion with increased
reusability.44
All these properties encouraged us to study the loading
of zeolite with nanogold (Figure 1). For use as a catalyst in
a simple route to synthesize pyrimido[4,5-b][1,6]naphthy-
ridine via a one-pot reaction between 6-amino-2-thioxo-
2,3-dihydropyrimidin-4(1H)-ones (1), aromatic aldehydes
(2) and 1-benzylpiperidin-4-one (3) (Scheme 1). The struc-
ture and morphology of the catalyst were determined by
X-ray diffraction (XRD) and transmission electron micros-
copy (TEM).
Results and discussion
Physicochemical characterization of the
nanocomposite
Low-angle XRD patterns corresponding to the prepared
zeolite–Au nanocomposite are shown in Figure 2. The sum
of the reflection intensities at 2θ of 15.5°, 24.0°, 28.0°,
32.0°, and 63.0° corresponding to the (450), (309), (207),
and (202) planes of a cubic crystal system is also shown in
Figure 2 for the prepared nanogold indicating the formation
of a cubic crystal of zeolite-nano Au. The intensities of the
peaks are relatively high being an indication of high crys-
tallinity. The formed zeolite is a mixture of sodium alu-
minum silicate and sodium aluminum oxide silicate, which
is confirmed from standard data for zeolites.
The method used to prepare the nanocomposite in this
work produced a uniform dispersion of small particles,
around 4–6
nm gold nanoparticles on zeolite, as shown in
the TEM image in Figure 3. The formation of small nano-
particles may help the incorporation of gold nanoparticles
within the zeolite framework as also indicated by XRD
measurements.
Chemistry
The uracil nucleobase has different tautomeric forms in
equilibrium, which is strongly dependent on the interaction
Figure 1. TEM micrograph of zeolite-doped AuNp used as a
catalyst for the preparation of pyrimido[4,5-b][1,6]naphthyridines.

Eid et al. 3
of these molecules with their environment. Knowledge
regarding this tautomerization in different environments
can provide insight into the influence of solvent/catalyst
effects on molecular stability. In this work, we have reported
the one-pot, three-component condensation reaction of
6-amino-2-thiouracil (1) with aromatic aldehydes (2) and
piperidinone (3) in ethanol using a zeolite–nanogold cata-
lyst to form fused pyrimido-naphthyridinones (4a–h) at
reflux temperature (Scheme 1).
From Table 1, it is very clear that the percentage of
the product 4a is greater in ethanol in the presence
of zeolite-gold as a nanocatalyst (entry 4), while in the
presence of zeolite, only a poor yield was obtained (entry
6). We noticed that in ethanol and using catalysts such as
nano ZnO, ZnO, or l-proline, the yields were higher (entries
1–3) compared to that obtained with C2H5OH/piperidine
(entry 5). The acidic medium, as acetic acid (entry 7), gives
a yield less than that in a basic medium.
The formation of the pyrimidonaphthyridine product (4)
is consistent with a Knoevenagel condensation, followed
by a Michael addition and cyclization, but the details of this
process have not been investigated. Compounds (4a–h)
were characterized by spectral and analytical methods. For
the compound 4a we find that its 1
HNMR shows the pres-
ence of a methine at δ = 5.33 (s) and a signal at δ = 6.37 (brs)
for other signals due to NH the NH groups of the uracil
moiety occurred at δ = 11.62 (s), and 12.04 (br), while sig-
nals due to the piperidinone ring moiety occurred at
δ = 2.35 (t), 2.51 (t), 2.89 (s), –NCH2 δ = 3.60 and sig-
nals for phenyl moieties appeared at δ = 6.78–7.96
(Figure 4). Full spectral and analytical data are given in
section “Experimental.” The different substituents on the
aryl groups lightly influenced the yields (Table 2).
Molecular docking
Genetic alteration of one or more components of the INK4
CDK4,6/cyclin D-retinoblastoma pathway is found in
more than half of all human cancers. Therefore, CDK4 is
an attractive target for the development of a novel anti-
cancer agent. Docking studies of compounds 4a and 4c
into the active site of human CDK4, 6/cyclin-D are con-
ducted. Compound 4a was docked into the binding pocket
of 2WGF; the theoretical binding mode between 4a and
HN
N
H
S
O
NH2
N
O
O
Ar HN
N
H
N
H
N
Ar
S
O
1 2a-h 3 4a-h
EtOH/nano Au-zeolite
reflux, 2hrs
4a= C6H5, 4b= 4-MeOC6H4, 4c= 3,4-(Meo)2C6H3, 4d= 3,4,5-(MeO)3C6H2,
4e= 4-FC6H4, 4f= 2,4-F2C6H3, 4g= 4-F3C6H2, 4h= 4-O2NC6H4
Scheme 1. Synthesis of pyrimido-naphthyridinone (4a–h).
Figure 2. XRD pattern of the zeolite–gold nanocomposite.
Figure 3. TEM micrograph of the zeolite-doped nanogold.
Table 1. Optimization of the reaction conditions for 4a.
Entry Solvent/catalyst Temperature (°C) Yield (%)a
1 EtOH/nanoZnO 80 90
2 EtOH/ZnO 80 85
3 EtOH/l-proline 80 87
4 EtOH/nano Au-zeolite 80 95
5 EtOH/piperidine 80 80
6 EtOH/zeolite 80 50
7 CH3COOH 110 78
a
Isolated yield based on thiouracil.

2WGF is shown in Figure 5. The NH group of thiouracil
in compound 4a formed interactions with the Met B213
residues (bond length: 2.17 Å), and there were arene–cat-
ion interactions between Arg P214 and added unsubsti-
tuted phenyl group.
In order to increase the activity of 4a, two methoxy groups
were added to the aromatic ring to give 4c. The theoretical
binding mode between 4c and 2WGF is shown in Figure 6.
Compound 4c adopted in the pocket of the 2WGF/CDK4/
cyclin-D. The two methoxy groups on the aromatic ring of 4c
bind at the 2WGF pocket. Detailed analysis showed that the
two methoxy-substituted ring of 4c formed arene–cation
interactions with the residues Arg B214, Arg P390, and Met
B212. It was shown that Asp P306 (bond length: 2.07
Å)
formed a hydrogen bond with the NH of thiouracil, and an
arene–cation interaction occurred between Arg A78 and the
phenyl group of 1-benzylpiperidin-4-one.
Cytotoxicity assay
Previously, it has been reported that the type of cancer cell
plays a crucial role in antitumor activity of tested com-
pounds. Upon screening our compounds against prolifera-
tion of Huh7, an in vitro model of human liver cancer
cells, our results showed that the tested compounds
showed different anti-proliferative activities against
Huh7, with IC50 values ranging from 22.5 to 87
µM.
Compounds 4c and 4a were the most cytotoxic inhibiting
HN
1
2
N
H
3
4
5
6
N
H
7
8
9
10
11
12
N
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
R2
28
R1
29
R3
30
S
31
O
32
1
H NMR: δ = 5.33(1H, s, H-10)
7.55(1H, br, NH-7).
13
C NMR: δ = 126.7(C-10)
Figure 4. NMR of synthesized compound 4a.
Table 2. Yields of compounds.
Entry Ar Product Yield (%)a
1 C6H5 4a 89
2 4-MeOC6H4 4b 75
3 3,4-(MeO)2C6H2 4c 89
4 3,4,5-(MeO)3C6H2 4d 90
5 4-FC6H4 4e 75
6 2,4-F2C6H3 4f 90
7 4-F3CC6H4 4g 87
8 4-O2NC6H4 4h 90
a
Comparative value to uracil.
Figure 5. Compound 4a was docked into the binding pocket
of 2WGF.
Figure 6. Compound 4c was docked into the binding pocket
of 2WGF.

Eid et al. 5
proliferation of Huh7 with IC50 values of 22.5 and 39 µM,
respectively, followed by compounds 4b and 4d (IC50
values 41 and 53 µM, respectively), while compound 4h did
not reveal any significant toxic effect on Huh7 (Figure 7).
Conclusion
Novel of pyrimido[4,5-b][1,6]naphthyridin-4(1H)-one (4a–h)
is prepared using a zeolite–nanogold catalyst, molecular
docking of compounds 4a and 4c into the active site of
human CDK4, 6/cyclin-D. Their in vitro evaluation as anti-
cancer agent shows that compounds 4c and 4a were the
most cytotoxic inhibiting proliferation of Huh7.
Experimental
Synthesis of nano Au-zeolite
The growth and ripening of gold nanoparticles were assem-
bled on the surface and cavities of zeolite networks. Zeolite
powder (Sigma-Aldrich, USA) was activated by annealing
for 5 h at 200 °C in vacuum oven to get rid of humidity and
activate the zeolite networks. 50 mL (0.01 M) gold chloride
and HAuCl4 (Sigma-Aldrich) solution were mixed with 1 g
activated zeolite under stirring at 60 °C for 3 h forming yel-
lowish solution. Heat up the solution till boiling and then
add 1 mL of 1% trisodium citrate (Sigma-Aldrich) solution,
then left to stir for 5 min till characteristic pink color of gold
nanoparticles formed. Centrifuge the solution at 10K r/min
for 30 min for precipitating Au–zeolite nanocomposite. The
obtained nanocomposite was dried in vacuum oven at 70°
for 8
h and stored in desiccator for further
characterization.57
Characterization of nano Au-zeolite
The particle size and the morphology of the prepared cata-
lyst were characterized by high TEM (Philips, The
Netherlands). The measuring mode of the sample in the
TEM instrument depends on its suspension in water fol-
lowed by ultrasonication for 600 s in ultra 8050-H Clifton.
It was then applied in the TEM instrument on 100 mesh
copper grade coated with carbon. Powder XRD patterns
were recorded with a PANalytical X’Pert PRO diffractom-
eter using a Cu Kα radiation source for the investigation of
the crystalline structure and phase.
Molecular docking
All molecular modeling calculations and docking studies
were performed using Molecular Operating Environment
(MOE), version 2009.10, Chemical Computing Group.
The program was used via the Windows XP operating sys-
tem installed on an Intel Pentium IV PC with a 2.9
MHz
processor and 512
RAM. The prepared compounds were
built using the MOE builder interface and subjected to
Figure 7. Cytotoxic effects of the tested compounds 4a–h against Huh7 cells.

energy minimization using MOPAC. The produced model
was subjected to a systematic conformational search,
where all items were set as default with a root mean square
(RMS) gradient of 0.01 kcal/mol and an RMS distance of
0.1 Å.
Biological assay
Cell culture. The Huh7, in vitro model of human liver can-
cer cell line, was obtained from ATCC (USA). Cells were
cultured in DMEM media (Gibco, USA) supplemented
with 10% fetal bovine serum (Gibco), antibiotics (2% pen-
icillin-streptomycin (100
IU/mL)), and 0.5% fungi zone
(Gibco). The cells were maintained in monolayer culture at
37 °C under a humidified atmosphere of 5% CO2. The cells
were sub-cultured by trypsinization (0.025% trypsin and
0.0025% EDTA; Gibco), and maintained in the Tissue Cul-
ture Laboratory at the Virology Immunology Unit, Can-
cer Biology Department, National Cancer Institute, Cairo
University, Egypt, with cryogenic banking of low-passage
cells to maintain uniformity of cell properties through the
study. Cell numbers and viabilities were monitored by stan-
dard Trypan blue dye exclusion procedures.58,59
Treatment of cells and colorimetric MTT assay. For investi-
gation of the cellular toxicity of all the synthesized com-
pounds against proliferation of Huh7 cells, 8 × 103
cells/
well were plated in a 96 tissue culture plate with 10%
DMEM. After 24
h, five different twofold dilutions of
compounds 4a–h (100, 50, 25, 12.5, and 6.25
µg/mL)
were tested against proliferation of Huh7 cells and the
plate was sealed and kept under standard conditions in a
CO2 incubator at 37
°C for 48
h. After the incubation
period, the plate was investigated for morphological
changes of the cells under an inverted microscope and
photos were captured (see Figure 8). MTT solution at a
concentration of 5 mg/mL PBS was added to all the wells,
which were then wrapped with aluminum foil and incu-
bated for 3–4 h at 37 °C.60
The medium was then removed
and 100
µL at DMSO was added to all the wells which
were then shaken for 10 min to dissolve the created forma-
zan crystals in the wells. The MTT formazan product was
identified via measuring the absorbance using an enzyme-
linked immunosorbent assay (ELISA) plate reader (BioTek
Model: ELX 800, USA), where positive and negative con-
trols were run in the plate. Negative control cells with
media only (untreated cells) were set as 100% viable,
while the positive control cells were subjected to osmotic
pressure using distilled water to give zero viability and
were used to subtract the background from all optical
density values. The ELISA plate reader measured the
absorbance at 570 and 620 nm as a reference wavelength.
The cells were monitored by phase-contrast microscopy at
40× magnification for any morphological changes. The
viability of the cells (%) in relation to the control wells
with untreated cells was calculated using the following
equation
Cellviability(%) 100
test
control
=
( )
×

A
A
where Atest is the absorbance of the test sample and Acontrol is
the absorbance of the control sample. The results were the
average of three wells and 100% viability was determined
from the negative control, that is, untreated cells.
For each compound concentration, five wells were used
(five replicate wells were prepared for each individual
dose). The average was calculated. Data are expressed as the
percentage of relative viability compared with the untreated
cells. The cytotoxicity dose was calculated as a dose induced
≈100% relative on viability.
Chemistry. Melting points were measured on a Gallenkamp
electrothermal melting point apparatus and are uncorrected.
Infrared (IR) spectra were recorded as KBr disks using a
Shimadzu FTIR Prestige 21 spectrophotometer. 1
H and 13
C
NMR spectra were recorded in DMSO-d6 at 300 MHz on a
Varian Mercury NMR spectrometer using TMS as the
internal standard. Chemical shifts (δ) are reported in parts
per million (ppm), and J values are given in hertz. The mass
spectra were recorded on a GCeMS-QP1000 EX mass
spectrometer at 70 ev. Elemental analyses were carried out
at the Micro-analytical Centre of Cairo University, Giza,
Egypt.
Figure 8. Cell morphology of Huh7: (a) untreated cell control, (b) Huh7 treated with a high concentration of 4c, and (c) Huh7
treated with a lower concentration of 4c. Images were taken at a magnification power of 100×.

Eid et al. 7
General procedure for the synthesis of
7-benzyl-5-aryl-2-thioxo-2,3,5,6,7,8,9,10-
octahydropyrimido[4,5-b][1,6]naphthyridin-
4(1H)-ones (4)
6-Amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1)
(0.3
mmol), 1-benzylpiperidin-4-one (0.3
mmol) (3), and
aromatic aldehyde (2) (0.3 mmol) were refluxed in ethanol
(15 mL)/zeolite-nano Au for 2 h. The mixture was filtrated
to isolate the catalyst and the solution was allowed to cool.
The resulting precipitate was washed with ethanol and
dried. Recrystallization from acetic acid gave crystals of
the desired compound.
7-Benzyl-5-phenyl-2-thioxo-2,3,5,6,7,8,9,10-octahydropyrimido
[4,5-b][1,6]naphthyridin-4(1H)-one (4a). Colorless powder
(89%); m.p. 297–298 °C. IR (KBr) (νmax/cm−1
): 3399, 3181,
1607, 1550. 1
H NMR (300 MHz, DMSO-d6): δ (ppm) 2.34
(t, J = 6 Hz, 2H, CH2), 2.51 (t, J = 6 Hz, 2H, CH2), 3.34
(s, 2H, CH2), 3.61 (s, 2H, CH2), 5.33 (s, 1H, CH), 6.37
(brs, 1H, NH), 6.78-7.96 (m, 10H, H-Ar), 11.62 (br, 1H,
NH), 12.04 (br, 1H, NH). 13
C NMR (75 MHz, DMSO-d6):
δ (ppm) 21.7, 31.2, 41.1, 52.7, 61.1, 78.6, 90.7, 125.7,
126.9, 127.5, 128.3, 128.7, 129.0, 129.1, 129.7, 138.4,
153.9, 162.1, 175.0. MS (EI, 70 eV): m/z (%): 403 (M + M+
,
25), 402 (M+
, 100). Anal. calcd for C23H22N4OS (402.15):
C, 68.63; H, 5.51; N, 13.92; found: C, 68.92; H, 5.60;
N, 13.99.
7-Benzyl-5-(4-methoxyphenyl)-2-thioxo-2,3,5,6,7,8,9,10-
octahydropyrimido[4,5-b][1,6]naphthyridin-4(1H)-one
(4b). Colorless powder (75%); m.p. 241–243
°C. IR (KBr)
(νmax/cm−1
): 3349, 3181, 1604, 1555. 1
H NMR (300 MHz,
DMSO-d6): δ (ppm) 2.08 (t, J = 6 Hz, 2H, CH2), 2.50
(t, J = 6 Hz, 2H, CH2), 3.43 (s, 2H, CH2), 3.45 (s, 2H, CH2),
3.68 (s, 3H, OCH3), 5.27 (s, 1H, CH), 6.72 (brs, 1H, NH),
6.75-6.94 (m, 9H, H-Ar), 7.95 (s, 2H, NH), 11.50 (s, 1H, NH).
MS (EI, 70
eV): m/z (%): 432 (M+
, 100). Anal. calcd for
C24H24N4O2S (432.16): C, 66.64; H, 5.59; N, 12.95; found:
C, 66.62; H, 5.53; N, 12.99.
7-Benzyl-5-(4,5-dimethoxyphenyl)-2-thioxo-2,3,5,6,7,8,9,10-
(4c). Colorless powder (89%); m.p. 218–220 °C. IR (KBr)
(νmax/cm−1
): 3351, 3181, 1623, 1545. 1
H NMR (300 MHz,
3.74 (s, 3H, OCH3), 3.80 ( s, 3H, OCH3), 5.30 (s, 1H, CH),
6.57 (brs, 1H, NH), 6.59-7.40 (m, 8H, H-Ar), 8.51 (s, 2H,
NH), 11.75 (s, 1H, NH). MS (EI, 70
eV): m/z (%): 463
(M + M+
, 27), 462 (M+
, 100). Anal. calcd for C25H26N4O3S
(462.17): C, 64.91; H, 5.67; N, 12.11; found: C, 64.72; H,
5.63; N, 12.07.
7-Benzyl-2-thioxo-5-(3,4,5-trimethoxyphenyl)-2,3,5,6,7,8,9,10-
(4d). Yellow powder (90%); m.p. 228–230
°C. IR (KBr)
(νmax/cm−1
): 3387, 3182, 1623, 1592. 1
H NMR (300 MHz,
3.67 (s, 3H, OCH3), 3.81 (s, 6H, 2OCH3), 5.33 (s, 1H, CH),
6.36 (brs, 1H, NH), 6.49–7.35 (m, 6H, H-Ar), 9.89 (brs,
1H, NH), 11.95 (brs, 2H, NH). 13
C NMR (75 MHz, DMSO-
d6): δ (ppm), 21.7, 33.0, 41.09, 52.7, 56.3, 61.1, 78.6, 90.9,
104.8, 107.2, 125.7, 126.9, 128.7, 129.1, 134.5, 136.0,
152.9, 154.2, 163.4, 173.2. MS (EI, 70 eV): m/z (%): 492
(M+
, 100), 493 (M + M+
, 28). Anal. calcd for C26H28N4O4S
(492.59): C, 63.40; H, 5.73; N, 11.37; found: C, 63.34; H,
5.70; N, 11.39.
7-Benzyl-5-(4-fluorophenyl)-2-thioxo-2,3,5,6,7,8,9,10-octahy-
dropyrimido[4,5-b][1,6]naphthyridin-4(1H)-one (4e). Yellow
powder (75%); m.p. 234–237
°C. IR (KBr) (νmax/cm−1
):
3371, 3193, 3109, 1620, 1588. 1
H NMR (300 MHz, DMSO-
d6): δ (ppm) 2.34 (t, J = 6 Hz, 2H, CH2), 2.67 (t, J = 6 Hz, 2H,
CH2), 3.41 (s, 2H, CH2), 3.60 (s, 2H, CH2), 5.29 (s, 1H, CH),
6.96 (brs, 1H, NH), 6.99-7.35 (m, 9H, H-Ar), 7.95 (s, 2H,
NH), 11.65 (s, 1H, NH). MS (EI, 70
eV): m/z (%): 420
(M+
, 100), 421 (M + M+
, 24). Anal. calcd for C23H21FN4OS
(420.51): C, 65.70; H, 5.03; N, 13.32; found: C, 65.62;
H, 5.08; N, 13.39.
7-Benzyl-5-(2,4-difluorophenyl)-2-thioxo-2,3,5,6,7,8,9,10-
(4f). Yellow powder (90%); m.p. 230–233
°C. IR (KBr)
(νmax/cm−1
): 3428, 3325, 3111, 1624, 1593. 1
H NMR
(300 MHz, DMSO-d6): δ (ppm) 2.34 (t, J = 6 Hz, 2H, CH2),
2.67 (t, J = 6 Hz, 2H, CH2), 3.07 (s, 2H, CH2), 3.60 (s, 2H,
CH2), 5.32 (s, 1H, CH), 6.38 (brs, 1H, NH), 6.63–7.35 (m,
8H, H-Ar), 8.96 (s, 1H, NH), 11.61 (brs, 2H, NH). 13
C
NMR (75 MHz, DMSO-d6): δ (ppm) 21.7, 31.2, 41.1, 52.7,
61.1, 78.6, 90.7, 125.7, 126.9, 127.5, 128.3, 128.7, 129.1,
129.3, 129.7, 138.4, 153.9, 154.3, 162.1, 163.2, 175.0. MS
(EI, 70
eV): m/z (%): 439 (M
+ M+
, 25), 438 (M+
, 100).
Anal. calcd for C23H20F2N4OS (438.50): C, 63.00; H, 4.60;
N, 12.78; found: C, 63.32; H, 4.83; N, 12.99.
7-Benzyl-2-thioxo-5-[4-(trifluoromethyl)phenyl]-
2,3,5,6,7,8,9,10-octahydropyrimido[4,5-b][1,6]naphthyridin-
4(1H)-one (4g). Colorless powder (87%); m.p. 288–290 °C.
IR (KBr) (νmax/cm−1
): 3500, 3320, 1605, 1560. 1
H NMR
(300 MHz, DMSO-d6): δ (ppm) 2.50 (t, J = 6 Hz, 2H, CH2),
2.73 (t, J = 6 Hz, 2H, CH2), 3.34 (s, 2H, CH2), 3.60 (s, 2H,
CH2), 5.40 (s, 1H, CH), 6.79 (brs, 1H, NH), 7.31-7.58 (m,
9H, H-Ar), 7.96 (s, 1H, NH), 11.89 (brs, 1H, NH), 12.11
(brs, 1H, NH). 13
C NMR (75
MHz, DMSO-d6): δ (ppm)
21.7, 31.2, 41.1, 52.7, 61.1, 78.6, 90.7, 123.9, 125.7, 126.9,
127.5, 128.3, 128.7, 129.0, 129.1, 129.7, 138.4, 153.9,
162.1, 173.3. MS (EI, 70
eV): m/z (%): 470 (M+
, 100).
Anal. calcd for C24H21F3N4OS (470.51): C, 61.27; H, 4.50;
N, 11.91; found: C, 61.92; H, 4.83; N, 11.99.
7-Benzyl-5-(4-nitrophenyl)-2-thioxo-2,3,5,6,7,8,9,10-
(4h). Colorless powder (90%); m.p. 300
°C. IR (KBr)
(νmax/cm−1
): 3340, 3140, 1600, 1541. 1
H NMR (300 MHz,
DMSO-d6): δ (ppm) 2.49 (t, J = 6 Hz, 2H, CH2), 2.50 (t,
J = 6 Hz, 2H, CH2), 3.56 (s, 2H, CH2), 3.60 (s, 2H, CH2),
5.42 (s, 2H, CH2), 6.77 (brs, 1H, NH), 7.35-8.14 (m, 9H,
H-Ar), 8.17 (s, 1H, NH), 11.80 (brs, 1H, NH). MS (EI,

70
eV): m/z (%): 447 (M+
, 100). Anal. calcd for
C23H21N5O3S (447.51): C, 61.73; H, 4.73; N, 15.65; found:
C, 61.75; H, 4.73; N, 15.69.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
ORCID iD
Elshimaa M Eid https://orcid.org/0000-0002-9916-7948
References
1. Han ZG, Zhang G, Jiang B, et al. J Comb Chem 2009; 11:
809–812.
2. Khakwani S, Aslam S, Mussadiq S, et al. Asian J Chem
2016; 28: 2601–2604.
3. Li Y, Liang J, Siu T, et al. Bioorg Med Chem Lett 2009; 19:
834–836.
4. Khakwani S, Aslam S, Shahi MN, et al. Asian J Chem 2017;
29: 27–30.
5. Tu XJ, Hao WJ, Ye Q, et al. J Org Chem 2014; 79: 11110–
11118.

6. Lavecchia G, Berteina-Raboin S and Guillaumet G.
Tetrahedron Lett 2004; 45: 6633–6636.
7. Gangjee A, Zeng Y, McGuire JJ, et al. J Med Chem 2002; 45:
5173–5181.
8. Marjani AP, Khalafy J, Arlan FM, et al. ARKIVOK V 2019;
1: 1–9.
9. Khosravi Z, Mohammadi H and Shaterian HR. J Chin Chem
Soc 2019; v: 1–8.

10. Moustafa MS, Al-Mousawi SM, Hilmy NM, et al. Molecules
2013; 18: 276–286.

11. Abdel Hafez NA, Farghaly TA, Al-Omar MA, et al. Eur J
Med Chem 2010; 45: 4838–4844.

12. Chen DM, Liu JY, Wei M, et al. Heterocycl Commun 2019;
25: 15–21.

13. Insuasty B, Becerra D, Quiroga J, et al. Eur J Med Chem
2013; 60: 1–9.

14. Gawande MB, Goswami A, Felpin FX, et al. Chem Rev
2016; 116: 3722–3811.

15. Zolfigol MA and Ayazi-Nasrabadi R. RSC 2016; 6: 69595.

16. Gandhi S, Nagalakshmi N, Baskaran I, et al. J Appl Polym
Sci 2010; 118: 1666–1674.

17. Babu SG and Karvembu R. Catal Surv Asia 2013; 17:
156–176.

18. Tandon PK and Singh SB. J Catal Catal 2014; 1: 1–14.

19. Singh SB and Tandon PK. J Energy Chem Eng 2014; 2:
106–115.

20. Yan K, Wu G, Jarvis C, et al. Appl Catal B Environ 2014;
148–149: 281–287.

21. Priecel P, Salami HA, Padilla RH, et al. Chin J Catal 2016;
37: 1619–1650.

22. Sun Y and Xia Y. Science 2002; 298: 2176–2179.

23. Yan J, Zhang X, Liu Y, et al. Nano Res 2019; 12: 1313–1320.
24. Lin C, Tao K, Hua D, et al. Molecules 2013; 18: 12609–12620.

25. Afrooz ARMN, Sivalapalan ST, Murphy CJ, et al.
Chemosphere 2013; 91: 93–98.

26. Carneiro JT, Savenije TJ, Moulijn JA, et al. J Photochem
Photobiol A Chem 2011; 217: 326–332.

27. Hereijgers BPC and Weckhuysen BM. Catal Lett 2011; 141:
1429–1434.

28. Alshammari A, Koeckritz A, Kalevaru VN, et al. Cat Chem
2012; 4: 1330–1336.

29. Conte M, Liu X, Murphy DM, et al. Phys Chem 2012; 14:
16279–16285.

30. Liu X, Conte M, Sankar M, et al. Appl Catal A Gen 2015;
504: 373–380.

31. de Sousa Martins LMDR, Carabineiro SAC, Wang J, et al.
Cat Chem 2017; 9: 1211–1221.
32. Chen S, Fu H, Zhang L, et al. Appl Catal B Environ 2019;
248: 22–30.

33. Ribeiro AC, de Sousa Martins LS, Carabineiro SAC, et al.
Molecules 2017; 22.

34. Dong Y, Luo J, Li S, et al. Catal Commun 2020; 133.

35. Ribeiro APC, de Sousa Martins LMDR, Carabineiro SAC,
et al. Appl Catal A Gen 2017; 547: 124–131.

36. Wan X, Zhou C, Chen J, et al. ACS Catal 2014; 4:
2175–2185.

37. Carabineiro SAC, de Sousa Martins LMDR, Avalos-Borja
M, et al. Appl Catal A Gen 2013; 467: 279–290.

38. De Almeida MP, de Sousa Martins LMDR, Carabineiro
SAC, et al. Catal Sci Technol 2013; 3: 3056–3069.

39. Rodrigues EG, Carabineiro SAC, Delgado JJ, et al. J Catal
2012; 285: 83–91.

40. Wang S, Zhao Q, Wei H, et al. J Am Chem Soc 2013; 135:
11849–11860.
41. García H and Navalón S. Applications in separations and cataly-
sis, 2018. © 2018 Wiley-VCH Verlag GmbH Co. KGaA.

42. Sun Z, Li G, Liu L, et al. Catal Commun 2012; 27: 200–205.
43. Wu R, Qian X, Zhou K, et al. Chem A 2013; 1: 14294–14299.

44. Saxena S, Singh R, Pala RGS, et al. RSC Adv 2016; 6:
8015–8020.

45. Xu LX, He CH, Zhu MQ, et al. Catal Lett 2007; 114:
202–205.

46. Xu LX, He CH, Zhu MQ, et al. Catal Commun 2008; 9:
816–820.

47. Huang J, Wang Y, Zheng J, et al. Appl Catal B Environ 2011;
103: 343–350.

48. Hosseini-Monfared H, Meyer H and Janiak C. J Mol Catal A
Chem 2013; 372: 72–78.

49. Van Speybroeck V, Hemelsoet K, Joos L, et al. Chem Soc
Rev 2015; 44: 7044–7111.

50. Jacobs PA, Dusselier M and Sels BF. Angew Chem—Int Ed
2014; 53: 8621–8626.
51. Pera-Titus M. Chem Rev 2014; 114: 1413–1492.

52. Javanbakht V, Ghoreishi SM, Habibi N, et al. Prot Met Phys
Chem Surfaces 2017; 53: 693–702.

53. Zihlif AM, Elimat Z and Ragosta G. J Compos Mater 2011;
45: 1209–1216.

54. Faghihian H, Moayed M, Firooz A, et al. Comptes Rendus
Chim 2014; 17: 108–117.

55. Kowalczyk P, Sprynskyy M, Terzyk AP, et al. J Colloid
Interface Sci 2006; 297: 77–85.
56. Pera-Titus M. J Phys Chem C 2011; 115: 3346–3357.

57. Salah El-Din TA, Elzatahry AA, Aldhayan DM, et al. Int J
Electrochem Sci 2011; 6: 6177–6183.
58. Phelan MC. Curr Protoc Cell Biol 2007; 36: 1.1.1–1.1.18.

59. Schmidt NJ and Emmons RW. DC 1989: 957–1065.
60. Mosmann T. J Immunol Methods 1983; 65: 55–63.
View publication stats
View publication stats

Preparation of pyrimido[4,5 b][1,6]naphthyridin-4(1 h)-one derivatives

Recommended

Recommended

More Related Content

What's hot

What's hot (19)

Similar to Preparation of pyrimido[4,5 b][1,6]naphthyridin-4(1 h)-one derivatives

Similar to Preparation of pyrimido[4,5 b][1,6]naphthyridin-4(1 h)-one derivatives (20)

Recently uploaded

Recently uploaded (20)

Preparation of pyrimido[4,5 b][1,6]naphthyridin-4(1 h)-one derivatives